Abstract：
Triptolide (TP) is the principal bioactive compound of Tripterygium wilfordii with significant anti-tumor, anti-inflammatory and immunosuppressive activities. However, its severe hepatotoxicity greatly limits its clinical use. The underlying mechanism of TP-induced liver damage is still poorly understood. Here, we estimate the role of the gut microbiota in TP hepatotoxicity and investigate the bile acid metabolism mechanisms involved. The results of the antibiotic cocktail (ABX) and fecal microbiota transplantation (FMT) experiment demonstrate the involvement of intestinal flora in TP hepatotoxicity. Moreover, TP treatment significantly perturbed gut microbial composition and reduced the relative abundances of Lactobacillus rhamnosus GG (LGG). Supplementation with LGG reversed TP-induced hepatotoxicity by increasing bile salt hydrolase (BSH) activity and reducing the increased conjugated bile acids (BA). LGG supplementation upregulates hepatic FXR expression and inhibits NLRP3 inflammasome activation in TP-treated mice. In summary, this study found that gut microbiota is involved in TP hepatotoxicity. LGG supplementation protects mice against TP-induced liver damage. The underlying mechanism was associated with the gut microbiota-BA-FXR axis. Therefore, LGG holds the potential to prevent and treat TP hepatotoxicity in the clinic.
摘要：
雷公藤甲素（TP）是雷公藤的主要生物活性化合物，具有显著的抗肿瘤作用，抗炎和免疫抑制活性。然而,其严重的肝毒性极大地限制了其临床应用。TP诱导的肝损伤的潜在机制仍然知之甚少。这里,我们评估了肠道菌群在TP肝毒性中的作用，并研究了所涉及的胆汁酸代谢机制。抗生素混合物（ABX）和粪便微生物群移植（FMT）实验的结果表明，肠道菌群参与TP肝毒性。此外，TP处理显著扰乱了肠道微生物组成并降低了鼠李糖乳杆菌GG(LGG)的相对丰度。补充LGG可通过增加胆盐水解酶（BSH）活性和减少增加的结合胆汁酸（BA）来逆转TP诱导的肝毒性。LGG补充上调TP处理小鼠的肝FXR表达并抑制NLRP3炎性体激活。总之,这项研究发现，肠道菌群参与TP肝毒性。LGG补充保护小鼠免受TP诱导的肝损伤。潜在的机制与肠道微生物群-BA-FXR轴有关。因此,LGG在临床上具有预防和治疗TP肝毒性的潜力。
